Plasma biomarkers to predict clinical outcomes of FOLFIRI plus ramucirumab (RAM) as second-line treatment for RAS wild-type metastatic colorectal cancer: JACCRO CC-16AR.
Authors: Yu Sunakawa, Hisateru Yasui, Manabu Shiozawa, Hiroyuki Takeda, Naoya Akazawa, Tamotsu Sagawa, Kazuhiro Shiraishi, Yoshihiro Okita, Hiroyuki Okuyama, Satoshi Yuki, Shoko Yanaka, Koutatsu Matsushima, Koki Miyakawa, Ayana Kobara, Wataru Ichikawa, Masashi Fujii, Akihito Tsuji
Journal: Journal of Clinical Oncology (2023)

177 Background: Angiogenesis-factors (AFs) have been reported as prognostic biomarkers for metastatic colorectal cancer (mCRC). RAS status in circulating-tumor DNA (ctDNA) is considered to be associated with resistance and potential efficacy of re-challenge treatment of anti-EGFR antibody in mCRC with RAS wild-type tumors. However, there were few evidence to prospectively evaluate the dynamic change of AFs and association of RAS status in ctDNA with clinical outcomes in anti-angiogenic therapies after anti-EGFR therapy for mCRC. Methods: Plasma samples were collected at pre-, day 15 after, and post-treatments in the pre-planned biomarker study of the JACCRO CC-16 trial which evaluated 2nd-line FOLFIRI plus RAM after anti-EGFR therapy in mCRC patients with RAS wild-type tumors (UMIN000034885). In 42 enrolled patients (median age, 68-y; ECOG PS 0/1, 31/11; all pts with left-sided tumors; median PFS, 6.8 months; median OS, 21.4 months; ORR, 10.3 %), some AFs (VEGF-A, VEGF-D, PlGF, HGF, IL-8, and angiopoietin-2) and RAS status in plasma were measured using the multiplex assay with Luminex technology and OncoBEAM RAS CRC Kit, respectively. The associations between clinical outcomes and AFs/ RAS status were investigated at timepoint of pre-treatment, using t-test and log-rank test. The median value was used as the cut-off value of AFs for high or low. The associations between AFs and RAS status were investigated using Brunner-Munzel test. Results: AFs and RAS status were evaluable in 38 and 41 patients, respectively. The OS was significantly longer in patients with IL-8 low compared to patients with IL-8 high (32.2 vs. 14.5 months, HR 0.36, p= 0.024). However, there was no difference in PFS between patients with IL-8 high and low. On the contrary, RAS mutations were detected at pre-treatment in 18 (44%) patients: KRAS codon12 83%, codon13 17%, codon61 67%, codon117 6%, codon146 11%, NRAS codon12 39%, codon61 78% in RAS mutations. Median PFS was 6.4 months in patients with RAS mutations in ctDNA, while it was 7.4 months in patients without RAS mutations (p = 0.10). Median OS was significantly longer in patients without RAS mutations compared to patients with RAS mutations (25.4 vs. 14.5 months, HR 0.39, p = 0.024). The ORR was 14.3% and 5.6% in patients without RAS mutations and with RAS mutations, respectively. In an exploratory analysis regarding the relationship between AFs and RAS status, IL-8 level was significantly higher in patients with RAS mutations than those without in ctDNA. Conclusions: This biomarker study demonstrated the associations between clinical outcomes and IL-8/ RAS status in blood before treatment in RAS wild-type mCRC treated with 2nd-line FOLFIRI plus RAM after anti-EGFR antibody therapy. Clinical trial information: UMIN000034885 .